A Critical Role for Syk Protein Tyrosine Kinase in Fc Receptor-Mediated Antigen Presentation and Induction of Dendritic Cell Maturation

Sedlik, Christine; Orbach, Daniel; Véron, Philippe; Schweighoffer, Edina; Colucci, Francesco; Gamberale, Romina; Ioan-Facsinay, A.; Verbeek, Sjef; Ricciardi‐Castagnoli, Paola; Bonnerot, Christian; Tybulewicz, Victor L. J.; Santo, James P. Di; Amigorena, Sebastián

doi:10.4049/jimmunol.170.2.846

Cited by 127 publications

(135 citation statements)

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“…Immature DCs, as well as DCs matured by using the cytokine mixture, were tested for the presence of both the inhibitory receptor Fc␥RIIb (by using anti-Fc␥RIIb antibody 2B6-FITC, MacroGenics) and the activating Fc␥R Fc␥RIIa (clone IV.3, Medarex, Annandale, NJ). Prior studies have shown that Fc␥RII is the most common Fc␥R expressed on human monocyte-derived DCs (17,20,22,27). However, these studies did not specifically examine the pattern of activating versus inhibitory isoforms of this receptor.…”

Section: Blocking Inhibitory Fc␥rs On Human Monocyte-derived Dcs Andmentioning

confidence: 99%

mentioning

confidence: 99%

“…In addition, targeting of antigens to Fc␥Rs on human DCs, including immune complexes and antibody-coated tumor cells, leads to enhanced generation of both CD4 ϩ and CD8 ϩ T cell responses in culture (6, 14-18). Therefore, the targeting of antigens to DCs by means of immune complexes can mediate both maturation of DCs and antigen presentation, leading to immunity that includes cross-presentation of tumors and autoantigens to CD8 ϩ T cells (17,(19)(20)(21)(22)(23).The Fc␥R system represents a balance of activating and inhibitory receptors that determines the outcome of immune complex-mediated inflammation and immunity (24). Prior studies by Kalergis and Ravetch (25) have shown that targeting immune complexes to DCs from mice genetically lacking inhibitory Fc␥RIIb can lead to enhanced generation of antigenspecific CD8 ϩ T cell immunity in vitro and in vivo.…”

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Selective blockade of inhibitory Fcγ receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells

Dhodapkar

Kaufman²,

Ehlers³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

213

208

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The final differentiation or maturation of dendritic cells (DCs) in response to environmental stimuli influences their ability to both initiate immunity and determine the quality of the response to antigens. Circulating immune complexes and cell-bound immunoglobulins present in normal human sera represent a potential stimulus for inadvertent DC activation in the steady state and during autoimmunity. Here, we show that selective blockade of the inhibitory Fc␥ receptor (Fc␥R) Fc␥RIIb with recently developed monoclonal antibodies leads to maturation of human monocytederived DCs, which depends on the presence of IgG in normal human plasma. Plasma, in the presence of an Fc␥RIIb blockade, caused the DCs to up-regulate the expression of costimulatory molecules and to produce the inflammatory mediator IL-12p70. Fc␥RIIb blockade of DCs loaded with tumor cells led to increased tumor-specific T cell immunity without the need for exogenous stimuli other than human plasma. Therefore, the activation status of DCs in the presence of normal human serum depends on the balance between activating and inhibitory Fc␥Rs and can be enhanced by new antibodies that react selectively with Fc␥RIIb. These data suggest an approach for modifying this balance to enhance immunity to immune complexes and antibody-coated tumor cells and to silence DC activation by immune complexes in autoimmune states.autoimmunity ͉ monoclonal antibody ͉ myeloma ͉ vaccination ͉ crosspresentation D endritic cells (DCs) are highly differentiated antigenpresenting cells that play a key role in the initiation and regulation of T cell immunity to pathogens and tumors while at the same time preventing immune responses against self-tissues or environmental antigens (1, 2). A critical property of DCs is that their ability to activate or inhibit immunity is linked to environmental stimuli, which determine their final differentiation or maturation status (3). Several stimuli, such as pathogens recognized by means of Toll-like receptors, CD40L, heat shock proteins, inflammatory cytokines, and innate lymphocytes, can lead to DC maturation and T cell immunity (2). However, under steady state, DCs must avoid inappropriate activation to prevent responses to self-antigens (''horror autotoxicus'') and harmless environmental antigens (4, 5). Specific pathways that prevent spontaneous DC activation are not as well understood as microbial and inflammatory stimuli.Circulating immune complexes and cell-bound immunoglobulins present in normal human sera represent a potential stimulus for DC activation in the steady state (6). The physiologic consequences of cell-bound IgG and immune complexes are modulated by a balance between activating and inhibitory Fc␥ receptors (Fc␥Rs) and include immune regulatory and inflammatory responses (7-10). Engagement of activating Fc␥Rs that contain an immune tyrosine-based activation motif on effector cells, including monocytes, neutrophils, natural killer cells, and mast cells, mediates phagocytosis, antibody-dependent cellmediated cytotoxicity, and r...

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Section: Blocking Inhibitory Fc␥rs On Human Monocyte-derived Dcs Andmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Selective blockade of inhibitory Fcγ receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells

Dhodapkar

Kaufman²,

Ehlers³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

213

208

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“…The importance of FcγRs on DCs has been further supported by recent studies showing that targeting antigen to activating FcγRs on DCs helps break tolerance in mice, while the ligation of inhibitory FcγR promotes tolerance [48,49] •• . The ability of IC to enhance antigen presentation depends on the recruitment of syk to the activating FcRs, as well as activation of PI3 kinase pathway [50,51]. FcγRs mediated activation leads to a distinct form of DC activation, including the induction of a type I interferon response program and proinflammatory cytokines [39,52].…”

Section: Role Of Fcγr Balance In Adaptive Immunitymentioning

confidence: 99%

Role of chaperones and FcγR in immunogenic death

Dhodapkar

2008

Current Opinion in Immunology

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Cell death under physiologic conditions does not lead to the induction of immunity. However recognition of stressed or opsonized cells can trigger immune responses. Recent studies have begun to illustrate the critical role of molecular chaperones such as inducible heat shock proteins in mediating immunogenicity of stressed cells. Immunity to opsonized cells depends in part on the engagement and the balance of activating and inhibitory FcγRs on antigen presenting dendritic cells. Understanding both these pathways of immunogenic cell death may yield novel approaches to regulate immunity. Two forms of immunogenic cell deathBillions of cells die each day and are replaced by newly differentiated progeny. Corpses of such dying cells are rapidly removed by phagocytes; do not elicit immunity and may induce tolerance. However under some settings, recognition of dying cells leads to inflammatory responses and immunity[1] • . Two aspects of such "immunogenic death" are the focus of this review. A common response to cellular stress is the transcriptional activation of molecular chaperones that belong to the class of inducible heat shock proteins (HSPs). Another setting wherein dying cells might induce immunity is when they are opsonized by antibodies due to antibody mediated recognition of determinants on dying cells. Such opsonized cells can be recognized by FcγR mediated pathways on antigen presenting cells (APCs). Below, we will discuss recent insights into how both of these pathways play an important role in regulating immunogenicity of dying cells and can be dysregulated in autoimmunity. Heat shock proteins (HSPs) and immunogenic cell deathHSPs are referred to as stress proteins or molecular chaperones, although most HSPs are constitutively expressed. Known best for their roles in regulating intracellular protein homeostasis, HSPs were immunologically implicated because of the observations that tumor-derived HSPs, although having no tumor-specific mutations, can immunize for tumor-specific T cell immunity [2] • . Efforts to explain the phenomenon have led to two

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“…In contrast, mature DCs can exhibit short as well as long contacts, which might be required for the initial scanning of MHC-peptide complexes followed by synapse formation and T-cell activation, respectively. [88][89][90][91][92][93] The formation of the immunological synapse requires both mature DC and peptide. Data from P Pierre (CIML, Marseille, France) showed that upon stimulation, DCs will accumulate newly synthesized ubiquitinated proteins in large cytosolic structures.…”

Section: Antigen Capture By DC In Situ and Interactions With Microbiamentioning

confidence: 99%

Dendritic cells: interfaces with immunobiology and medicine. A report from the Keystone Symposia Meeting held in Keystone, 3–8 March 2003

Mohty

Gaugler

2003

Leukemia

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Dendritic cells (DCs) are the most potent antigen-presenting cells in vitro and in vivo. They play a key role in the initiation of the immune response and are considered promising targets for immunotherapy. The recent DC Keystone Symposia, organized by Ralph M Steinman, Anne O'Garra and Jacques Banchereau, was held on 3-8 March 2003 in Keystone (CO, USA). This multidisciplinary meeting developed various areas related to the DC biology including: (i) DC and the control of immunity vs tolerance; (ii) DC maturation and manipulation for immunotherapy in vivo; and (iii) antigen capture by DC in situ and interactions with microbial pathogens. The aim of this report is to present some of the highlights developed during the meeting and debated among the DC community. Leukemia (2003) IntroductionDendritic cells (DCs) are the most potent antigen-presenting cells in vitro and in vivo. They play a key role in the initiation of the immune response and are considered promising targets for immunotherapy. [1][2][3][4][5][6] The recent DC Keystone Symposia, organized by Ralph M Steinman, Anne O'Garra and Jacques Banchereau, was held on 3-8 March 2003 in Keystone (CO, USA). As in previous years, it was dedicated to the encounter of scientists and clinicians involved in the field of DC biology and immunotherapy. The major topics were covered by invited lectures from outstanding experts. This year, some sessions were organized jointly with another simultaneous Keystone Symposia: Cell biology of the immune response organized by Ira Mellman, Richard Flavell and Ralph M Steinman. The poster sessions provided participants with the opportunity to present their data. In addition to the plenary sessions, the authors of the best posters were invited to participate and present their work in the afternoon workshops. The productive and friendly atmosphere of this high-standard meeting was maintained by the organizers and participants throughout the symposium. This multidisciplinary meeting developed various areas related to the DC biology. This report will focus on some of these aspects including: (i) DC and the control of immunity vs tolerance; (ii) DC maturation and manipulation for immunotherapy in vivo; and (iii) antigen capture by DC in situ and interactions with microbial pathogens. The aim of this report is not to develop detailed results presented during the meeting, but rather to summarize some of the major issues debated among the DC community. DC and the control of immunity vs toleranceDifferent lines of evidence suggest that DCs, through preprogrammed different subsets or 'flexibility' within one subset, can either control immunity or mediate antigen-specific tolerance. Data from YJ Liu group (DNAX; Palo Alto, CA, USA) highlighted the role of interactions between epithelial cells and DCs in initiating allergic inflammation. They show that human thymic stromal lymphopoietin, highly expressed by epithelial cells, can potently activate myeloid CD11c+ DCs with induction of proallergic cytokines (IL-4, IL-5, IL-13 and TNF-alpha) and...

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A Critical Role for Syk Protein Tyrosine Kinase in Fc Receptor-Mediated Antigen Presentation and Induction of Dendritic Cell Maturation

Cited by 127 publications

References 40 publications

Selective blockade of inhibitory Fcγ receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells

Selective blockade of inhibitory Fcγ receptor enables human dendritic cell maturation with IL-12p70 production and immunity to antibody-coated tumor cells

Role of chaperones and FcγR in immunogenic death

Dendritic cells: interfaces with immunobiology and medicine. A report from the Keystone Symposia Meeting held in Keystone, 3–8 March 2003

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